In:
Otolaryngology–Head and Neck Surgery, Wiley, Vol. 132, No. 1 ( 2005-01), p. 55-62
Abstract:
Head and neck squamous cell carcinoma (HNSCC) is notoriously resistant to chemotherapy. The sphingolipid ceramide and its analogs have been demonstrated to exert antitumor activity in many cell types; however, the effectiveness of these analogs has been limited by potency and solubility. This study focuses on the effects of novel highly soluble cationic pyridinium‐ceramides, alone and in combination with various chemotherapeutic agents, on cell survival, telomerase activity, and cell cycle arrest in HNSCC cell lines in vitro. METHODS The concentration of pyridinium‐ceramides and chemotherapeutic agents that inhibited cell growth by 50% (IC 50 ) was determined by MTT cell survival assays. The cell cycle profiles were determined by flow cytometry. Telomerase activity was determined by telomerase repeat amplification protocol (TRAP) assay. RESULTS Treatment of the human UM‐SCC‐22A (SCC of the hypopharynx) cells, as well as various other HNSCC cell lines, with C 6 ‐Pyr‐Cer resulted in the inhibition of cell survival with an IC 50 concentration of approximately 250 to 300 nM at 96 hours, whereas its IC 50 was greater than 1000 nM in noncancerous Wi‐38 human lung fibroblasts, and adult human epidermal keratinocytes. Moreover, treatment with C 6 ‐Pyr‐Cer also resulted in cell cycle arrest in G0/G1, which correlated with a significant inhibition of telomerase activity in UM‐SCC‐22A cells. Additional results demonstrated that the combination of C 6 ‐Pyr‐Cer with gemcitabine (GMZ) or doxorubicin (DOX), which have the lowest IC 50 concentrations among various chemotherapeutic drugs in these cells, enhances the effects of these drugs in the inhibition of telomerase and cell growth. CONCLUSIONS These data suggest that the novel C 6 ‐Pyr‐Cer with high solubility and bioavailability may lead to the development of new therapeutic strategies that target telomerase for the treatment of HNSCC.
Type of Medium:
Online Resource
ISSN:
0194-5998
,
1097-6817
DOI:
10.1016/j.otohns.2004.08.015
Language:
English
Publisher:
Wiley
Publication Date:
2005
detail.hit.zdb_id:
2008453-5
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